The general purpose of this project is to study the molecular and cellular mechanisms underlying the phenomena of opiate tolerance, dependence and withdrawal using the LC as a cellular model for chronic opiate studies. Specific aims are: I. To study mechanisms underlying acute desensitization and tolerance to opiates in the locus coeruleus of naive and morphine-dependent rats. These studies will be done using electrophysiological (conventional intracellular and whole-cell recordings in brain slices) and biochemical techniques. II. To study the effects of chronic administration of naltrexone (an opiate antagonist) and buprenorphine (a mixed agonist-antagonist) on the locus coeruleus. Both biochemical and electrophysiological techniques will be employed. III. To investigate further the glutamatergic mechanisms underlying opiate dependence and withdrawal. Electrophysiological and microdialysis techniques will be employed. The phenomenon of long-term desensitization to glutamate in locus coeruleus neurons will be studied in both naive and morphine-dependent animals. We also propose to extend studies on the role of glutamate in the development of opiate dependence. IV. To study the role of glutamatergic mechanisms in the action of various systemically-administered agents used in the suppression of opiate withdrawal. Microdialysis techniques will be employed to study the effect of systemically and/or locally applied agents on glutamate levels in the LC. The proposed research on the mechanisms underlying opiate tolerance, dependence and withdrawal should lead to the development of newer and better methods for the treatment of withdrawal symptoms in opiate-addicted humans.